Hypomethylating Agents and Venetoclax for Acute Myeloid Leukemia Relapsed After Hematopoietic Stem Cell Transplant.

BACKGROUND: Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. PATIENTS AND METHODS: We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. RESULTS: CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. CONCLUSION: These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.

Association between CYP3A4, CYP3A5 and ABCB1 genotype and tacrolimus treatment outcomes among allogeneic HSCT patients.

Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.

Sirolimus Is an Acceptable Alternative to Tacrolimus for Graft-versus-Host Disease Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide.

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor HCT. A phase II study from the Moffitt Cancer Center substituting sirolimus (Siro) for Tac in this prophylactic regimen reported comparable rates of grade II-IV acute GVHD (aGVHD). Many centers have substituted Siro for Tac in this setting based on a preferable side effect profile, although comparative data are limited. In this study, we retrospectively compared outcomes in haplo-HCT with PTCy/Siro/MMF versus haplo-HCT with PTCy/Tac/MMF. The study cohort included all consecutive patients receiving haploidentical donor T cell-replete peripheral blood stem cell (PBSC) HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. A total of 423 patients were included, of whom 84 (20%) received PTCy/Siro/MMF and 339 (80%) received PTCy/Tac/MMF. The median age for the entire cohort was 54 years (range, 18 to 78 years), and the median follow-up was 30 months. The Siro group had a higher proportion of patients age ≥60 years (58% versus 34%; P < .01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV aGVHD (45% versus 47%; P = .6) at day +100 or chronic GVHD (cGVHD) (47% versus 54%; P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better in the Tac group (odds ratio, .30; 95% confidence interval, .1 to .83; P = .02), with a median time to engraftment of 17 days versus 18 days in the Siro group, but platelet engraftment was similar in the 2 groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on aGVHD or cGVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease-free survival, or overall survival after PBSC haplo-HCT. These findings suggest that Siro is a comparable alternative to Tac in combination with PTCy/MMF for GVHD prophylaxis, with overall similar clinical outcomes despite delayed engraftment after peripheral blood stem cell haplo-HCT. Although Tac remains the standard of care, Siro may be substituted based on the side effect profile of these medications, with consideration of patient medical comorbidities at HCT.

Allogeneic hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a CIBMTR analysis.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines.

The sole curative therapy for myelodysplastic syndrome (MDS) is allogeneic hematopoietic cell transplantation (HCT). Here this therapeutic modality is reviewed and critically evaluated in the context of the evidence. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of MDS experts comprising transplantation and nontransplantation physicians developed consensus treatment recommendations. This review summarizes the standard MDS indications for HCT and addresses areas of controversy. Recent prospective trials have confirmed that allogeneic HCT confers survival benefits in patients with advanced or high-risk MDS compared with nontransplantation approaches, and the use of HCT is increasing in older patients with good performance status. However, patients with high-risk cytogenetic or molecular mutations remain at high risk for relapse. It is unknown whether administration of novel therapies before or after transplantation may decrease the risk of disease relapse in selected populations. Ongoing and future studies will investigate revised approaches to disease risk stratification, patient selection, and post-transplantation approaches to optimize allogeneic HCT outcomes for patients with MDS.

Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113 AML patients.

We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.

Large Scale Ex Vivo Expansion of γδ T cells Using Artificial Antigen-presenting Cells.

Higher γδ T cell counts in patients with malignancies are associated with better survival. However, γδ T cells are rare in the blood and functionally impaired in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and interleukin-2 (IL-2). Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K-562 CD3scFv/CD137L/CD28scFv/IL15RA quadruplet artificial antigen-presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a Good Manufacturing Practice (GMP) compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of coculture with aAPC, which exhibited central (47%) and effector (43%) memory phenotypes. In addition, >90% of the expanded γδ T cells expressed NKG2D, although they have low cell surface expression of PD1 and LAG3 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded γδ T cells were effective in killing target cells. Our results demonstrate that large-scale ex vivo expansion of donor-derived γδ T cells in a GMP-like setting can be achieved with the use of quadruplet aAPC and zol/IL-2 for clinical application.

Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.

Outcomes Following Intolerance to Tacrolimus/Sirolimus Graft-versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation.

Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis regimen following allogeneic hematopoietic cell transplantation (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. This study was conducted to assess the outcomes of patients with TAC/SIR intolerance and guide their subsequent management. We retrospectively analyzed transplantation outcomes of consecutive adult patients at Moffitt Cancer Center who underwent allogeneic HCT with TAC/SIR as GVHD prophylaxis between 2009 and 2018. TAC/SIR intolerance was defined as discontinuation of either TAC or SIR due to toxicity before post-transplantation day +100. A total of 777 patients met the inclusion criteria. The median duration of follow-up was 22 months (range, 0.2 to 125 months). Intolerance occurred in 13% (n = 104) of the patients at a median of 30 days (range, 5 to 90 days). The most common causes of intolerance were acute kidney injury (n = 53; 51%), thrombotic microangiopathy (n = 31; 28%), and veno-occlusive disease (n = 23; 22%). The cumulative incidence of grade II-IV acute GVHD at 100 days was 50% (95% CI, 39% to 64%) in the TAC/SIR-intolerant patients and 25% (95% CI, 22% to 29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, the incidence of grade II-IV 4 acute GVHD was significantly higher in the TAC/SIR-intolerant patients (hazard ratio [HR], 2.40; 95% CI, 1.59 to 3.61; P < .0001). Similarly, in multivariate analyses, the TAC/SIR-intolerant patients had a higher incidence of chronic GVHD (HR, 1.48; 95% CI, 1.03 to 2.12; P = .03). The nonrelapse mortality (NRM) at 1 year was 47% (95% CI, 38% to 59%) in the TAC/SIR-intolerant patients and 12% (95% CI, 10% to 15%) in those tolerant to the regimen (P < .0001). The 2-year relapse-free survival was 35% (95% CI, 25% to 44%) in the TAC/SIR-intolerant patients and 60% (95% CI, 57% to 65%) in the TAC/SIR-tolerant patients (HR, 2.30; 95% CI, 1.61 to 3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31 to 100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early; 95% CI, 59% to 94%) versus 33% (late; 95% CI, 21% to 50%) (P = .001), as well as the cumulative incidence of NRM at 61% (early; 95% CI, 48% to 77%) versus 35% (late; 95% CI, 24% to 51%) (P = .006). Most patients who developed TAC/SIR intolerance were switched to an alternative 2-drug regimen (71 of 104; 68%), most commonly mycophenolate mofetil in addition to continuing TAC or SIR (68 of 71; 96%). Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to a higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. The use of single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted.

A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD.  This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Cytokine Release Syndrome Following Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide.

Post-transplantation cyclophosphamide (PTCy) is a safe and efficacious graft-versus-host-disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT) from a haploidentical (haplo) donor. Cytokine release syndrome (CRS) is a common complication of this platform. Early fever post-haplo-HCT using bone marrow grafts is associated with higher CD3+ cell dose and CRS. However, the impact of CD3+ and CD34+ cell dose on CRS post-haplo-HCT using peripheral blood stem cell (PBSC) grafts is unknown. Our goals were to evaluate the incidence of CRS following PBSC transplantation (PBSCT) and to identify factors that can be modified to prevent the development of severe CRS in this setting. In 271 patients, we investigated factors associated with the development of CRS following haplo-PBSCT and examined the impact of CRS on clinical outcomes. Ninety-three percent of the patients developed CRS of any grade post-haplo-PBSCT. In multivariate analysis, severe CRS (grade 3-4 versus grade 0-1) was associated with higher nonrelapse mortality (hazard ratio [HR], 6.42; 95% confidence interval [CI], 2.68 to 15.39; P < .001), worse 1-year overall survival (HR, 3.40; 95% CI, 1.63 to 7.08; P = .005), and worse disease-free survival (HR, 4.02; 95% CI, 1.99 to 8.08; P < .001). Moderate to severe CRS (grade 2-4) did not impact 1-year relapse or acute GVHD (grade II-IV and III-IV) at 100 days (P = .71 and .19, respectively). Importantly, higher CD3+ cell dose, but not CD34+ cell dose, predicted a higher incidence of grade 2-4 CRS (HR, 1.20; 95% CI,1.07 to 1.36; P = .003) and grade 3-4 CRS (HR, 1.40; 95% CI, 1.05 to 1.86; P = .022). Both older age (HR, 8.57; 95% CI, 1.73 to 42.36; P < .001) and non-total body irradiation-based reduced-intensity conditioning with fludarabine/melphalan (HR, 15.38; 955 CI, 2.06 to 114.67; P < .001) were predictive of grade 3-4 CRS. Overall, we observed that severe CRS (grade 3-4) negatively affected transplantation outcome, and that higher CD3 cell dose was associated with the development of any grade CRS and severe CRS.

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Managing multiple myeloma in a resource-limited region: Diagnosis and treatment in Armenia.

Multiple myeloma (MM) is the second most common blood cancer in adults leading to 117,000 deaths every year. Major breakthroughs in clinical research of the past decades transformed the diagnosis and treatment of MM improving the survival rates and overall quality of life of patients. Unfortunately, scientific advancements are not distributed equally around the globe leading to disparities in the treatment outcomes between different regions of the world. Management of MM in low- and middle-income countries represents a big challenge for healthcare providers considering the economic, technological, and infrastructural restraints in comparison to developed countries. Many standards of practice, including diagnostic tools and therapeutic regimens, are not available in developing regions of the world. As an example of an upper-middle-income country, Armenia has been witnessing considerable progress in the diagnosis and treatment of MM, including but not limited to the establishment of autologous stem cell transplant (ASCT), accessibility to modern anti-myeloma medications, and improved diagnostic and monitoring workup. Despite significant improvements, there is still a need for refinement in the management of MM. The aim of this review article is to discuss the latest developments and the current diagnosis and treatment of MM in Armenia as an example of a resource-limited region.

Expansion and Enrichment of Gamma-Delta (γδ) T Cells from Apheresed Human Product.

Although Vγ9Vδ2 T cells are a minor subset of T lymphocytes, this population is sought after for its ability to recognize antigens in a major histocompatibility complex (MHC)-independent manner and develop strong cytolytic effector function that makes it an ideal candidate for cancer immunotherapy. Due to the low frequency of Gamma-Delta (γδ) T cells in the peripheral blood, we developed an effective protocol to greatly expand a highly pure γδ T cells drug product for first-in-human use of allogeneic γδ T cells in patients with acute myeloid leukemia (AML). Using healthy donor apheresis as an allogenic cell source, the lymphocytes are isolated using a validated device for a counterflow centrifugation method of separating cells by size and density. The lymphocyte-rich fraction is utilized, and the γδ T cells are preferentially activated with zoledronic acid (FDA-approved) and interleukin (IL)-2 for 7 days. Following the preferential expansion of γδ T cells, a clinical-grade magnetic cell-separation device and TCRαß beads are used to deplete contaminating T-cell receptor (TCR)αß T cells. The highly enriched γδ T cells then undergo a second expansion using engineered artificial antigen-presenting cells (aAPCs) derived from K562 cells-genetically engineered to express single-chain variable fragment (scFv) for CD3 and CD28, 41BBL (CD137L) and IL15-RA-together with zoledronic acid and IL-2. Seeding all day-7 enriched γδ T cells in co-culture with the aAPCs facilitates the manufacture of highly pure γδ T cells with an average fold expansion of >229,000-fold from healthy donor blood.

An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p < 0.001); disease-free survival (DFS) (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p < 0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p < 0.001). Multivariate analysis (MVA) revealed no differences in outcomes between the Fav and IM groups, thus they were combined. On MVA, patients in the Adv risk group had the highest risk of relapse (HR 1.47 p ≤ 0.001) and inferior DFS (HR 1.35 p < 0.001) and OS (HR 1.39 p < 0.001), even using myeloablative conditioning or in those without the pre-HCT measurable-residual disease. Novel approaches to mitigate relapse in this high-risk group are urgently needed.

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults.

Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.